Cytokines are secreted proteins that regulate cellular growth and differentiation. These factors are especially important in regulating immune and inflammatory responses, and are critical in the pathogenesis of autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, psoriasis, allergy and asthma. Targeting cytokines and cytokine signaling represent successful new strategies in treating these diseases, underscoring the need to better understand the molecular basis of cytokine action as it relates to the pathogenesis of immune-mediated disease. A critical means through which cytokines exert their effect is activation of receptor-associated Janus kinases, or JAKs, and the activation of a family of transcription factors called STATs (signal transducers and activators of transcription); this has been the focus of our work for the last two decades. One important action of cytokines in which STAT proteins play a key role is the differentiation of different subsets of lymphocyte to attain distinct fates. CD4+ T follicular helper cells (TFH) are critical for the formation and function of B cell responses to infection or immunization, but also play an important role in autoimmunity. The factors that contribute to the differentiation of this helper cell subset are incompletely understood, although several cytokines including IL-6, IL-21, and IL-12 can promote TFH cell formation. Yet, none of these factors, nor their downstream cognate STATs, have emerged as nonredundant, essential drivers of TFH cells. This suggests a model in which multiple factors can contribute to the phenotypic characteristics of TFH cells. Because type I IFNs are often generated in immune responses, we set out to investigate whether these factors are relevant to TFH cell differentiation. Type I IFNs promote Th1 responses, thus one possibility was that these factors antagonized TFH-expressed genes. However, we show that type I IFNs induced B cell lymphoma 6 (Bcl6) expression, the master regulator transcription factor for TFH cells, and CXCR5 and programmed cell death-1 (encoded by Pdcd1), key surface molecules expressed by TFH cells. In contrast, type I IFNs failed to induce IL-21, the signature cytokine for TFH cells. The induction of Bcl6 was regulated directly by STAT1, which bound to the Bcl6, Cxcr5, and Pdcd1 loci. These data suggest that type I IFNs (IFN-&#945;/&#946;) and STAT1 can contribute to some features of TFH cells but are inadequate in inducing complete programming of this subset. Also critical to immune homeostasis are various types of regulatory cells; this too has been a focus of our work. Genetic polymorphisms within in the BACH2 gene are associated with numerous autoimmune and allergic diseases including asthma, Crohn's disease, celiac disease, vitiligo, multiple sclerosis and type 1 diabetes. We showed that BACH2 is required for efficient formation of regulatory (Treg) cells and that absence of Bach2 in mice is associated with lethal autoimmunity. Assessment of the genome-wide function of BACH2, using Chip-seq, revealed that it represses genes associated with effector cell differentiation. Consequently, its absence during Treg polarization resulted in inappropriate diversion to effector lineages. In addition, BACH2 constrained full effector differentiation within Th1, Th2 and Th17 cell lineages. These findings identify BACH2 as a key regulator of CD4 helper T-cell differentiation that prevents inflammatory disease by controlling the balance between tolerance and immunity. IL-10 is another key mechanism that preserves immune tolerance. Mutations of IL10 and the gene encoding its receptor result in human autoimmunity manifested by inflammatory bowel disease. Polymorphisms of the IL10 locus are associated with autoimmunity but also susceptibility to infection. Consequently, understanding the regulation of this key cytokine is important for understanding immune homeostasis. This year, we showed that innate immune cells, specifically NK cells switch from predominantly producing IFN-gamma, a cytokine with proinflammatory and antimicrobial functions, to producing the IL-10 during the course of viral infection. In contrast to the sustained open profile of the Ifng gene, during the course of infection NK cells acquired permissive histone modifications in the IL10 locus. This occurred concomitant with NK cell proliferation. Ongoing studies are investigating how the chromatin landscape is modified in innate lymphoid cells versus T cells and what factors drive these differences. A major focus of the laboratorys efforts over the past several years has been to approach the issue of helper T cell specification using new tools that allow genomic views of differentiating cells. A powerful technique has been chromatin immunoprecipitation and massive parallel sequencing (ChIP-seq). This technique can be used to understand genome-wide actions of transcription factors and also to understand epigenetic changes associated with cellular specification. This is relevant as a major factor governing the stability of cellular phenotype is the epigenetic landscape, which permits or restricts access to critical genes. Genes themselves though comprise just a small fraction of the genome (2%); most of the genome appears to be switches that regulate gene expression. We used this technology to map active enhancer elements in T helper 1 (Th1) and Th2 cells. Our data establish that STAT proteins have a major impact on the activation of lineage-specific enhancers and the suppression of enhancers associated with alternative cell fates. Transcriptome analysis further supports a functional role for enhancers regulated by STATs. Importantly, expression of lineage-defining master regulators in STAT-deficient cells fails to fully recover the chromatin signature of STAT-dependent enhancers. Thus, these findings point to a critical role of STATs as environmental sensors in dynamically molding the specialized enhancer architecture of differentiating cells. More recently, we have used this approach to identify regions of the genome that are subject to intense regulation. These regions have been termed stretch or superenhancers.